Adenosine modulates a variety of physiological functions through interactions with A1 and A2 adenosine receptors, where agonists can mediate inhibition and stimulation, respectively, of adenylate cyclase. Adenosine analogs, in particular the N6-substituted compounds, are more potent at A1 receptors than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. Xanthines are classical antagonists for adenosine receptors and many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A1 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenylxanthines are very water insoluble, but incorporation of polar aryl substituents, such as para-sulfo or para-carboxy to increase solubility, results in marked reduction in potency and selectivity. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the class of adenosine receptors. Receptor agonists and agents that enhance influx of sodium into brain synaptoneurosomes enhance turnover of phosphatidylinositols resulting in accumulations of inositol phosphates. Such receptor agonists and sodium agents concomittantly augment accumulations of cyclic AMP elicited by forskolin and by A2-adenosine receptors. Phorbol esters, which like the diacylglycerides formed during phosphatidylinositol metabolism, activate protein kinase, also augment accumulations of cyclic AMP both in brain tissue and in pheochromocytoma cells.